Dr. John Christianson is a F32-funded research associate with extensive knowledge the neural mechanisms underlying resilience and vulnerability to anxiety and fear behavior. Past research has identified that psychological variables, including behavioral control over stress and safety signals during stress lead to a resilience from stress-induced anxiety. Furthermore, he has identified causal roles for the medial prefrontal cortex and insular cortex, respectively, in these stress-mitigating effects. His immediate goal is to advance his academic and technical skills in order to enact an independent research program studying the neural basis of safety learning and fear inhibition by safety. The K99/R00 proposal is a key component in this pursuit. Career Development Plan: Dr. Christianson<s proposed training activities consist of: 1) training in electrophysiological techniques for the study of neuroplasticity, 2) attendance and participation at scientific meetings in which the scientific content revolves around learning and memory, 3) mentoring and training of undergraduate and graduate students on independent research projects within the sponsors< laboratories. Environment: The research will be conducted in the University of Colorado<s Psychology & Neuroscience Department and the Institute of Behavioral Genetics. Co-sponsors, Drs Steven Maier and Donald Cooper are established investigators in the fields of stress, learning & memory and neuroplasticity. Both labs have a sufficient extramural funding to support the proposed research and excellent records mentoring postdoctoral fellows. Furthermore, the laboratory space is adequate and equipment state-of-the art. Research: The proposed studies test two complementary hypotheses relating safety learning. Safety learning is a Pavlovian process by which sensory stimuli come to predict the non-occurrence of an aversive event. First: Safety learning occurs in the insular cortex. This will be tested in several ways including i) pharmacological inhibition of insular cortex at the times when a rat is learning or recalling the safety cue, ii.) in vitro whole-cell patch clamp assessment of intrinsic excitability of amygdala-projecting insular cortex neurons and iii.) multiple- electrode assessment of plasticity within insular cortex synapses. Second: Exposure to uncontrollable stress, a laboratory model of posttraumatic stress disorder (PTSD), will interfere with learning and expression of safety signals. This hypothesis will be tested by interpolating uncontrollable stress before or after the safety learning. Together these complementary approaches will lead to a significant advancement in understanding of the neural mechanisms underlying safety and provide a paradigm for studying pathological safety learning as occurs in PTSD. PUBLIC HEALTH RELEVANCE: Learning the difference between danger and safety is critical to survival, yet in some psychiatric conditions this process fails. Without veridical detection of safety, someone may express fear or anxiety even when the environmental cues indicate that danger is unlikely. The proposed work tests the hypothesis that the insular cortex is a critical contributor to safety learning and that neuroplastic changes in the insular cortex underlie the storage and recall of safety memory. This work has important implications for the treatment and diagnosis of posttraumatic stress disorder and other conditions that involve heightened fear and anxiety.